The interleukin 36 (IL-36) cytokines IL-36α, IL-36β, and IL-36γ (formerly IL-1F6, IL-1F8, and IL-1F9) are interleukin-1 (IL-1) family members that bind to the IL-36 receptor (IL-36R) (formerly IL-1Rrp2 or IL-1RL2) and use IL-1 receptor accessory protein (IL-1RAcP) as a coreceptor to stimulate intracellular signals similar to those induced by IL-1 (Towne et al., J. Biol. Chem., 279(14): 13677-13688 (2004)). IL-1F5 is an IL-1 family member that has been shown to act as an antagonist of IL-36R, and is now referred to as IL-36Ra (Dinarello et al., Nat. Immunol., 11(11): 973 (2010)).
IL-36α, IL-36β, and IL-36γ are highly expressed in several tissues, including internal epithelial tissues that have been exposed to pathogens, and in skin. Expression of IL-36Ra and IL-36α is significantly up-regulated in IL-1β/TNF-α-stimulated human keratinocytes, and IL-36Rα and IL-36γ mRNAs are overexpressed in psoriasis skin lesions. Elevated IL-36α mRNA and protein expression also have been observed in chronic kidney disease (Ichii et al., Lab Invest., 90(3): 459-475 (2010)). Both murine bone marrow-derived dendritic cells (BMDCs) and CD4+ T lymphocytes constitutively express IL-36R and respond directly to IL-36α, IL-36β, and IL-36γ by producing proinflammatory cytokines (e.g., IL-12, IL-1β, IL-6, TNF-α, and IL-23) inducing a more potent stimulatory effect than other IL-1 cytokines (Vigne et al., Blood, 118(22): 5813-5823 (2011)).
Transgenic mice overexpressing IL-36α in keratinocytes exhibit a transient inflammatory skin disorder at birth that renders mice highly susceptible to a 12-O-tetradecanoylphorbol 13-acetate-induced skin pathology resembling human psoriasis (Blumberg et al., J. Exp. Med., 204(11): 2603-2614 (2007); and Blumberg et al., J. Immunol., 185(7):4354-4362 (2010)). Furthermore, IL-36R-deficient mice are protected from imiquimod-induced psoriasiform dermatitis (Tortola et al., J. Clin. Invest., 122(11): 3965-3976 (2012)). These results strongly suggest a role for IL-36 in certain inflammatory disorders of the skin.
IL-36 cytokines also have been implicated in certain severe forms of psoriasis, including pustular psoriasis, generalized pustular psoriasis (GPP), and palmo-plantar pustulosis (PPP)) (see, e.g., Town, J. E. and Sims, J. E., Curr. Opin. Pharmacol., 12(4): 486-90 (2012); and Naik, H. B. and Cowen, E. W., Dermatol Clin., 31(3): 405-425 (2013)). Pustular psoriasis is a rare form of psoriasis characterized by white pustules surrounded by red skin. Generalized pustular psoriasis is a severe, systemic form of pustular psoriasis that has a high risk of fatality, while palmo-plantar pustulosis is a chronic form of pustular psoriasis that affects the palms and soles of the feet. Current treatments for pustular psoriasis, GPP, and PPP include oral retinoids and topical steroids, but these treatments exhibit poor efficacy and severe side effects.
There is a need for antagonists of IL-36R (e.g., an antibody) that bind IL-36R with high affinity and effectively neutralize IL-36R activity. The invention provides such IL-36R-binding agents.